The “Three-Tier Regulatory Network” of Orthokeratology in Myopia Control: Evidence Weight of Underlying Mechanisms, Controversies, and New Perspectives for Clinical Translation--A Review

Longhui Han,1,2 Shangkuan He,2 Shuting Dong,2 Yuying Lu,2 Minglian Zhang1,2 1Hebei Eye Hospital, Hebei Provincial Clinical Research Center for Eye Diseases, Xingtai, Hebei, 054001, People’s Republic of China; 2Department of Ophthalmology, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of ChinaCorrespondence: Longhui Han, Hebei Eye Hospital, Hebei Provincial Clinical Research Center for Eye Diseases, Xingtai, Hebei, 054001, People’s Republic of China, Tel +8615631901373, Email [email protected] Minglian Zhang, Hebei Eye Hospital, Hebei Provincial Clinical Research Center for Eye Diseases, Xingtai, Hebei, 054001, People’s Republic of China, Tel +8615631901999, Email [email protected]: Orthokeratology (Ortho-K) is an important optical intervention for myopia control in adolescents. Its proposed mechanism has evolved from the traditional “peripheral defocus” hypothesis to a complex network of multi-pathway collaborative regulation. By analyzing the latest literature from 2023 to 2025, this review systematically outlines the core mechanisms of Ortho-K in slowing myopia, and innovatively proposes a “Initial driver - Intermediate signal integration - Terminal effect” three-tier regulatory network model based on evidence weight. This model covers: 1) the initial driver tier (the highest evidence weight, including direct lens stimulation on the cornea and peripheral retinal myopic defocus, the core trigger of the regulatory cascade); 2) the intermediate signal integration tier (corneal nerve reflex, retinal-choroidal structural and hemodynamic changes, responsible for signal conversion and amplification); 3) the terminal effect tier (scleral remodeling, the final common pathway of myopia inhibition). The review emphasizes the interaction and prioritization between optical defocus, corneal biomechanics, neurovascular regulation, and molecular signaling pathways, while also assessing the evidence levels of each pathway. Additionally, it addresses key controversies in the current field (such as individual response differences) and explores future research directions in combination with cutting-edge technologies like artificial intelligence (AI) personalized design and single-cell sequencing. Finally, based on mechanistic studies, it provides feasible translational recommendations for optimizing clinical practice and personalized treatment strategies.Keywords: orthokeratology, myopia control, mechanism network, hierarchical regulation, individual response, clinical translation, artificial intelligence